Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

MDMA (3,4-methylenedioxymethamphetamine) is widely used recreationally and is under investigation as an adjunct to psychotherapy, notably for post-traumatic stress disorder. Methylphenidate and modafinil are clinically used stimulants for attention-deficit/hyperactivity disorder and narcolepsy respectively, but are also misused as cognitive enhancers. The pharmacology of MDMA differs from classical stimulants: MDMA releases serotonin and oxytocin in addition to noradrenaline, whereas methylphenidate and modafinil primarily augment dopaminergic and noradrenergic transmission without strong serotonergic or oxytocinergic effects. Earlier studies indicate MDMA produces prosocial, empathogenic mood changes and endocrine markers of serotonergic activity, but direct within-subject comparisons with other orally administered stimulants have been limited and used only a few outcome measures. Dolder and colleagues designed a double-blind, placebo-controlled, randomized cross-over study to characterise and directly compare the acute autonomic, subjective, emotional, sexual, and endocrine effects of single oral doses of MDMA, methylphenidate, and modafinil in healthy volunteers. The primary a priori hypothesis was that MDMA—but not methylphenidate or modafinil—would produce prosocial/empathic feelings and elevate plasma oxytocin. A secondary aim was to compare methylphenidate and modafinil effects on mood and cognition, complementing prior work in stimulant users.

The study used a double-blind, placebo-controlled, randomized cross-over design with four experimental sessions per participant: 125 mg MDMA, 60 mg methylphenidate, 600 mg modafinil, and placebo. Twenty-four healthy volunteers (12 men, 12 women), mean age 22.6 ± 3.0 years, completed all sessions. Session order was counterbalanced and washout periods were at least 7 days. All female participants used oral contraceptives and were tested during the follicular phase (day 2–14) to reduce cyclical variability. The study was approved by local ethics committees and registered (ClinicalTrials.gov NCT01951508). Key inclusion criteria were age 18–45 years and BMI 18–27 kg/m2; exclusion criteria included personal or first-degree family history of psychiatric disorder, significant physical illness, tobacco smoking >10 cigarettes/day, and lifetime illicit drug use >5 times (exceptions noted for occasional cannabis). Drug screening was performed at screening and before each test day. The majority of participants had little or no prior experience with MDMA or other illicit drugs. Experimental sessions began in the morning with baseline measures and insertion of an indwelling intravenous catheter. Study drugs were administered at 09:45. Autonomic and subjective measures were repeatedly assessed up to 6 h post-administration; blood for endocrine assays and plasma concentrations was sampled at multiple time points. A task-related fMRI scan took place during the expected peak effects (results to be published separately). Face emotion recognition (FERT) was assessed at 2.5 h post-dose and the Sexual Arousal and Desire Inventory (SADI) at 3 h. Adverse effects were measured acutely (up to 6 h) and at 24 h. Primary and secondary outcome measures included autonomic variables (blood pressure, heart rate, tympanic temperature) with peak rate-pressure product as the main autonomic outcome; multiple subjective scales (visual analogue scales (VAS), Adjective Mood Rating Scale (AMRS), State-Trait Anxiety Inventory (STAI), ARCI, and 5D-ASC); endocrine assays (plasma cortisol, prolactin, oxytocin, vasopressin); the FERT (accuracy and misclassification analyses); SADI subscales; and plasma pharmacokinetics (Cmax, Tmax). Statistical analyses used repeated-measures ANOVA with drug as the within-subject factor and Tukey post hoc tests, with Friedman ANOVAs and Wilcoxon tests for non-normally distributed VAS data. Multiple comparisons within VAS and AMRS were Bonferroni-adjusted; significance was set at p < 0.05.

All 24 participants completed every session. Autonomic measures showed that all active drugs produced comparable sympathomimetic stimulation: systolic and diastolic blood pressure, heart rate, body temperature, and peak rate-pressure product increased after MDMA, methylphenidate, and modafinil compared with placebo. MDMA produced markedly greater pupil dilation (dark pupil size and reduced constriction amplitude) than methylphenidate and modafinil; the other two drugs produced only small pupil increases. On subjective measures, MDMA produced robust positive and prosocial effects. On VAS ratings MDMA increased any drug effect, good drug effect, drug liking, happiness, openness, trust, feeling close to others, ‘‘I want to be with other people,’’ and ‘‘I want to hug someone’’ relative to placebo. MDMA also increased wellbeing, emotional excitation and extraversion on the AMRS, reduced state anxiety on the STAI, and raised relevant ARCI subscale scores (amphetamine-group, morphine, and pentobarbital-chlorpromazine-alcohol groups). By contrast, methylphenidate produced significant but smaller increases in ‘‘any drug effect,’’ ‘‘good drug effect,’’ and drug liking, produced modest increases in openness and closeness, and increased state anxiety on the STAI. Modafinil produced no significant subjective mood effects versus placebo on the VASs or AMRS. Endocrine assays showed that only MDMA produced marked increases in plasma cortisol, prolactin, and oxytocin relative to placebo and to the other active drugs. Methylphenidate produced a slight cortisol increase; modafinil had no effect on cortisol, prolactin, oxytocin, or vasopressin. None of the active treatments altered vasopressin concentrations. On the Facial Emotion Recognition Task (complete data missing for two subjects), a repeated-measures ANOVA found a significant main effect of drug on accuracy for fearful faces (F3,63 = 7.38, p < 0.001). Post hoc tests showed MDMA significantly impaired recognition of fearful faces compared with placebo (p < 0.001), methylphenidate (p < 0.01), and modafinil (p < 0.05). MDMA also increased misclassification of emotions as happy (main effect F3,63 = 3.35, p < 0.05; MDMA vs placebo p < 0.05). In contrast, methylphenidate and modafinil increased misclassifications as angry (main effect F3,63 = 3.38, p < 0.05) but did not change overall recognition accuracy for the emotions. Sexual arousal and desire measured by the SADI (one subject missing) showed that only MDMA increased scores on the Evaluative (p < 0.001), Physiological (p < 0.001), and Motivational (p < 0.05) factors relative to placebo; the Negative/Aversive factor was unchanged. MDMA raised specific items such as ‘‘tingly all over,’’ ‘‘sensitive to touch,’’ ‘‘enthusiastic,’’ ‘‘warm all over,’’ ‘‘heart beats faster,’’ and ‘‘seductive.’’ The investigators noted that these effects could reflect somatic drug effects that coincide with sensations typically associated with sexual arousal. Pharmacokinetic data (Cmax ± SEM, Tmax ± SEM) were reported: MDMA Cmax 192 ± 8.7 ng/ml, Tmax 3.7 ± 0.3 h; MDA Cmax 9.1 ± 0.4 ng/ml, Tmax 5.7 ± 0.2 h; HMMA Cmax 69.1 ± 10.0 ng/ml, Tmax 4.2 ± 0.3 h. Methylphenidate Cmax 27.0 ± 2.1 μg/ml, Tmax 3.2 ± 0.3 h; modafinil Cmax 13.2 ± 0.5 μg/ml, Tmax 3.3 ± 0.3 h. Adverse effects up to 6 h were increased after all active drugs versus placebo, with the most frequent complaints being lack of appetite, dry mouth, and headache. Modafinil produced adverse effects that persisted to 24 h (insomnia, headache, loss of appetite). No severe adverse events occurred.

Dolder and colleagues interpret their results as showing that MDMA produces an acute effect profile that is qualitatively distinct from the stimulant-type drugs methylphenidate and modafinil when doses are matched for overall cardiostimulant activity. MDMA uniquely increased markers of positive mood and prosocial feelings (wellbeing, happiness, trust, closeness to others, wanting to be with others), reduced state anxiety, impaired recognition of fearful faces and increased happy misclassifications on the FERT, and produced marked increases in cortisol, prolactin, and oxytocin. These findings are congruent with MDMA’s pharmacology—release of serotonin and oxytocin in addition to noradrenaline—and with earlier research reporting empathogenic effects and serotonergic endocrine responses. The stimulant drugs shared sympathomimetic cardiovascular effects with MDMA but differed in subjective and endocrine profiles. Methylphenidate produced modest subjective stimulant effects and increased state anxiety, whereas modafinil at the high single dose used (600 mg) produced pronounced cardiovascular and adverse effects but no consistent subjective mood changes; modafinil and methylphenidate increased misclassification of emotions as angry on the FERT. The investigators emphasise that the within-subject, blinded, four-condition design provides direct and internally controlled comparisons that reduce between-subject and between-study confounds. Several limitations acknowledged by the authors could affect interpretation. Only a single dose of each drug was tested, so findings apply to the specific relatively high doses used and may not generalise across dose ranges. Differences in pharmacokinetics between substances may bias comparisons despite broadly comparable Tmax values in this study. The use of many psychometric instruments raises the possibility of chance findings; the principal hypothesis regarding greater socioemotional effects of MDMA was confirmed, but some scale-specific differences (STAI, ARCI, SADI) are considered exploratory. Regarding the SADI, the authors note that somatic and generalised pleasurable sensations induced by MDMA may have influenced sexual arousal ratings in the absence of explicit sexual stimuli, so whether MDMA produces true sexual arousal versus nonspecific somatic effects remains unclear. In summary, the study team concludes that MDMA produces distinct acute subjective, emotional, sensual/sexual, and endocrine effects compared with methylphenidate and modafinil at doses that produce similar sympathomimetic stimulation. Modafinil produced comparable cardiovascular stimulation but little subjective mood effect and had adverse effects that lasted up to 24 h. The authors suggest these differential profiles are consistent with the differing pharmacologies of the substances and note that further work, including dose–response studies and pharmacokinetic considerations, would help refine these comparisons.